With interest, we read the paper by Hasan et al. (1), who showed that inhibition of TANK-binding kinase 1 (TBK1) by Compound II has beneficial effects in a mouse model of autoimmune disease. Similarly, TBK1 inhibition by the small molecule drug amlexanox has been shown to mediate favorable metabolic and anti-inflammatory effects in mouse models of diabetes, obesity (2, 3) and multiple sclerosis (4).

Consequently, it is plausible that pharmacological reduction of cellular TBK1 activity to 50% or less might have similar cellular effects as TBK1 haploinsufficiency. Long-term pharmacological TBK1 inhibition, as proposed for the treatment of autoimmune diseases (1, 4), could thus pose a risk of causing ALS or FTD. Also, in terms of a two-hit-model, chronic TBK1 inhibition may be able to trigger ALS/FTD in individuals exposed to an environmental insult or with a genetic predisposition who would otherwise not have developed ALS or FTD during their lifetime.

Experimental proof that pharmacological TBK1 inhibitors increase the risk for neurodegenerative diseases is currently lacking. Nevertheless, the existing unequivocal genetic evidence that TBK1 haploinsufficiency causes ALS/FTD with high penetrance, in our opinion, strongly suggests the need to critically reconsider currently ongoing or planned clinical trials that are based on pharmacological TBK1 inhibition.